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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

According to OECD 414, Lanolin alcohols was administered by gavage to three dose groups each of twenty-four (twenty-three for the 300 mg/kg bw/day dose group) time mated rats, between Days 5 and 19 of gestation at dose levels of 100, 300 and 1000 mg/kg bw/day (Croda, 2014). A further group of twenty-four time mated females was exposed to the vehicle only (Arachis oil) to serve as a control.

Clinical signs, body weight change, food and water consumptions were monitored during the study. All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.

There were no unscheduled deaths. Females treated with 1000 and 300 mg/kg bw/day showed isolated incidences of increased salivation between Days 6 and 13. No such effects were detected in females treated with 100 mg/kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable test item formulation and in isolation are considered not to be of toxicological significance. One female treated with 1000 mg/kg bw/day also showed fur loss between days 16 and 20. Observations of this nature are commonly observed and in isolation is not considered to be related to test item toxicity. No adverse effect on body weight development was detected and statistical analysis of the data did not reveal any significant intergroup differences. At necropsy, no macroscopic abnormalites were found.

There was no treatment related effects on in utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and post-implantation losses. There were also no adverse effects on pre-implantation losses or in sex ratio. Females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in the number of corpora lutea. This intergroup difference was not dose related and was considered to be incidental and unrelated to treatment due to ovulation and mating occurring prior to the administration of the test item. Females treated with 1000 mg/kg bw/day also showed a statistically significant reduction in pre-implantation loss. A reduction in this parameter is considered not to represent an adverse effect of treatment therefore the intergroup difference was considered of no toxicological importance.

For all dose groups, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies. The type of external, visceral and skeletal anomalies, were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations. Statistical analysis of the data did not reveal any significant differences.

In conclusion, the oral administration of Lanolin Alcohols to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day, did not result in any toxicologically significant adverse effects. The NOAEL was therefore considered to be >= 1000 mg/kg bw/day for maternal toxicity and developmental toxicity.

Lanolin Fatty Acids (CAS 68424-43-1) was tested in a prenatal developmental toxicity study according to OECD Guideline 414 (Whitlow, 2013). The test substance was applied by gavage to Han-Wistar rats. 22 female animals per dose were treated with 100, 300 or 1000 mg/kg bw/day test substance dissolved in corn oil on Days 6-15 of gestation. Control animals (22 females per dose) received the vehicle. Observations and examinations of the animals included clinical signs, body weight, food consumption and post-mortem examinations, with emphasis on the uterus and its content.

All females survived until the scheduled necropsy on day 21 post coitum. No clinical symptoms or signs were observed at any dose level during the study that were considered to be related to the test item. No test item-related changes were observed in the amount of food consumed during the study. Absolute body weight and body weight gain were not affected by treatment with the test item. The relevant reproduction data (post-implantation loss and number of fetuses per dam) were not affected by treatment with the test item. No findings were observed at any dose level during macroscopical examination.

No findings were observed during external examination of the fetuses in any group. No test item-related effects on the sex ratio and body weights of the fetuses were noted in any group. There were no findings seen during visceral examination that were considered to be related to maternal administration of the test item. Severe kidney pelvic dilatation was seen in one fetus in the group given 1000 mg/kg bw/day, and severely malpositioned testis was recorded for one fetus in the group given 100 mg/kg bw/day. However, as both instances were isolated findings, these were not considered to be test item-related. Examination of bone and cartilage abnormalities and variations revealed no test substance related effects. Furthermore no test substance related effects were observed after examination of ossification and supernumerary ribs. Examination of additional cartilage variations revealed that costal cartilage not reaching sternum was statistically significantly increased at 1000 mg/kg bw/day on a litter and on a fetus basis. This incidence has been observed in this strain and is therefore not considered to be test item-related. All further findings were within the range of the historical control data or did not increase in a dose-dependent manner. There were no findings observed that were considered to be related to maternal administration of the test item.

In conclusion, a NOAEL of 1000 mg/kg bw was derived for prenatal development and for maternal toxicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 Aug - 11 Nov 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(adopted 22 January 2001)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japenese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147, (24 November, 2000)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of the Government of the United Kingdom
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley Crl:CD (SD) IGS BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, UK
- Weight at study initiation: 214 to 299 g
- Housing: The animals were housed individually in solid-floor polypropylene cages with stainless steel lids furnished with softwood flakes (Datesand Ltd., Cheshire, UK)
- Diet: pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan UK, Oxon, UK); ad libitum
- Water: drinking water; ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 50±20
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18 Aug 2013 To: 05 Sept 2013
Route of administration:
oral: gavage
Vehicle:
other: Arachis oil BP
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was prepared at the appropriate concentrations as a solution in Arachis oil BP. The stability and homogeneity of the test item formulations were previously determined by Harlan Laboratories Ltd., Shardlow, UK Analytical Services (Harlan Laboratories Ltd., Project Number 41301173). Results showed the formulations to be stable for at least twenty days. Formulations were therefore prepared once and stored at approximately +4°C in the dark.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken of each test item formulation and were analyzed for concentration of Lanolin Alcohols at Harlan Analytical Laboratory, Shardlow. The test item concentration in the test samples was determined by HPLC with UV detection using an external standard technique. The results indicate that the prepared formulations were within ± 2% of the nominal concentration.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- The day that positive evidence of mating was observed was designated Day 0 of gestation.
Duration of treatment / exposure:
Day 5 - 19 of gestation
Frequency of treatment:
daily
Duration of test:
15 days
No. of animals per sex per dose:
24 (except for the intermediate treatment group: Only 23 animals were used in the intermediate treatment group as upon delivery of the animals, one female was found to have a damaged eye. This female was unsuitable to be used on the study and was humanely killed.)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were chosen based on previous toxicity data.
- Other: The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are delieved to be of value in predicting the likely toxicity of the test item to man.
Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Following arrival, all animals were examined for overt signs of toxicity, ill-health or behavioral changes once daily during the gestation period. Additionally, during the dosing period, observations were recorded immediately before and soon after dosing and one hour post dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: on Day 3 of gestation (before the start of treatment) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation. Body weights were also recorded for animals at terminal kill (Day 20).

FOOD CONSUMPTION: Yes
- Time schedule for examinations: for each individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily by visual inspection of the water bottles for any overt changes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
- All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number, position and type of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Placental weight: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Visceral examinations: Yes: half per litter
Statistics:
Female body weight change, food consumption and gravid uterus weight: Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, on alternative multiple comparison test.
All caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.
Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis nonparametric analysis of variance and Mann-Whitney ‘U’ test.
Probability values (p) are presented as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 (not significant)
Indices:
Pre- and post-implantation losses
Historical control data:
Historical control data from several former embryofetal development toxicity studies were provided, giving information on skeletal findings, visceral examination, and reproductive data.
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: Observed effects on body weight, food consumption, clinical signs, pre-implantation loss and number of corpora lutea. However, these effects were considered not to represent an adverse effect or to be incidental and unrelated to treatment.

Details on maternal toxic effects:
Mortality: There were no unscheduled deaths (table 3).

Clinical Observations: Females treated with 1000 and 300 mg/kg bw/day showed isolated incidences of increased salivation between Days 6 and 13 (table 2). No such effects were detected in females treated with 100 mg/kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable test item formulation and in isolation are considered not to be of toxicological significance. One female treated with 1000 mg/kg bw/day also showed fur loss between days 16 and 20 (table 2). Observations of this nature are commonly observed in isolation are not considered to be related to test item toxicity. Therefore, no treatment-related effects were found.

Body Weight: No adverse effects on body weight development were detected. Statistical analysis of the data did not reveal any significant intergroup differences (table 3).

Food Consumption: Females treated with 1000 mg/kg bw/day showed a statistically significant increase in food consumption between Days 14 and 17 (table 4). The increase in food consumption is not considered to represent an adverse effect of treatment. Furthermore, intergroup differences on body weight were considered of no toxicological significance.

Water Consumption: Daily visual inspection of water bottles did not reveal any overt intergroup differences.

Pathological examinations: No macroscopic abnormalities were detected.

Females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in the number of corpora lutea (table 5). This intergroup difference was not dose-related and was considered to be incidental and unrelated to treatment due to ovulation and mating occurring prior to the administration of the test item. Females treated with 1000 mg/kg bw/day also showed a statistically significant reduction in pre-implantation loss (table 5). A reduction in this parameter is considered not to represent an adverse effect of treatment therefore the intergroup difference was considered of no toxicological importance.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Litter Data and Litter Placenta and Fetal Weights:
There were no treatment-related effects on in utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and post-implantation losses. There was also no adverse effect in sex ratio.
For all dose groups, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies (tables 6, 7 and 8). The type of external, visceral and skeletal anomalies, were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations. Statistical analysis of the data did not reveal any significant differences.
Therefore, no treatment-related effects were detected in the uterine parameters examined, in fetal viability or in growth and development.
Key result
Remarks on result:
not determinable because of methodological limitations
Key result
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Summary of female performance

 

Control group

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Initial group size

24

24

23

24

Pregnant animals

22

24

20

24

 

Table 2: Summary incidence of daily clinical observations

Dose level [mg/kg bw/day]

Number of animals

Clinical observations

Number of animals showing effect (day of observation)

0

24

no abnormalities detected

-

100

24

no abnormalities detected

-

300

23

Increased salivation

3 (6, 9)

1000

24

Increased salivation

15 (6-13)

Generalized fur loss

1 (16-20)

 

Table 3: Group mean values on pregnant females

Parameter

Control group

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of dams examined

22

24

20

24

Mortality of dams [%]

0.0

0.0

0.0

0.0

Body weight gain [g]

Day 5–20 of gestation

121.3±15.5

125.6±15.6

124.4±16.4

126.8±14.7

Gravid uterus weight [g]

82.3±9.7#

80.3±14.6

80.3±9.3

81.2±11.2

#: n=21 for gravid uterus weight. Gravid uterus weight not recorded for one female in error.

 

 

Table 4: Group mean food consumption values

Dose level [mg/kg bw/day]

Number of dams examined

Food consumption (g/rat/day) between days of gestation

3-5

5-8

8-11

11-14

14-17

17-20

0

22

25.6±2.0

21.0±2.2

23.0±2.6

24.7±1.9

25.7±2.2

25.2±2.1

100

24

25.0±2.2

21.8±3.4

23.3±2.6

25.2±3.4

26.1±2.6

27.2±5.0

300

20

25.5±2.5

21.5±2.2

23.0±3.3

25.2±2.8

26.9±3.6

26.5±3.9

1000

24

25.4±3.1

22.0±2.0

24.7±2.3

26.2±2.0

27.9±2.6**

27.4±3.0

** Significantly different from control: p** < 0.01

 

Table 5: Group mean litter data values

Parameter

Control group

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of corpora lutea

14.9±1.5

14.4±1.8

13.0±1.5***

13.5±2.0**

Number of implants

13.5±1.7

12.8±2.6

12.5±1.2

13.1±1.8

Total number of live implants

12.8±2.4

12.6±2.7

12.2±1.4

12.5±2.0

Total number of embryonic/fetal deaths

1.0±1.6

0.3±0.5

0.3±0.4

0.6±1.6

Pre-implantation loss [%]

8.8±7.9

12.0±13.7

4.0±4.9

2.8±5.5**

Post-implantation loss [%]

5.8±12.0

1.0±2.7

2.1±3.7

4.0±10.4

Total number of litters

22

24

20

24

Mean fetal weight[g]

4.073±0.156

4.157±0.196

4.217±0.156

4.166±0.262

Mean placental weight[g]

0.559±0.049

0.553±0.067

0.577±0.037

0.582±0.056

** Significantly different from control: p** < 0.01

*** Significantly different from control: p*** < 0.001

Table 6: Summary incidence of fetal external findings

Parameter

0 (Control)

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of foetuses examined

281

303

244

301

Small fetus

0

1

1

1

Omphalocele

1

0

0

0

Pale

0

0

1

1

Total number of foetuses with fetal external findings (% of foetuses with fetal external findings)

1 (0.4)

1 (0.4)

2 (0.8)

2 (0.7)

 

Table 7: Summary incidence of fetal visceral findings

Parameter

0 (Control)

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of foetuses examined

146

157

128

157

Total number of foetuses with fetal visceral findings (% of foetuses with fetal external findings)

51 (33.5)

53 (34.3)

34 (26.5)

70 (45.1)

 

Table 8: Summary incidence of fetal skeletal findings

Parameter

0 (Control)

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of foetuses examined

135

146

117

144

Total number of foetuses with fetal skeletal findings (% of foetuses with fetal external findings)

117 (88.6)

123 (84.7)

96 (81.5)

114 (78.8)

 

NOTE: a fetus may appear in more than one category

 

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05 Mar - 27 Nov 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Guidelines (Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Teratology (2-1-18), Agricultural Production Bureau, dated November 24, 2000).
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: RccHanTM:WIST(SPF)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B. V., Horst, The Netherlands
- Age at study initiation: 11 weeks
- Weight at day 0 (post coitum): 196-246 g (females)
- Housing: single housing in Makrolon type-3 cages after the acclimatisation period
- Diet: Pelleted standard Harlan Teklad 2018C (batch no. 56/12) rodent maintenance diet (Provimi Kliba AG, Kaiseraugst, Switzerland), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The solutions were prepared daily. The test substance was weighed into a glass beaker on a tared Mettler balance and the vehicle was added. The mixtures were stirred using a magnetic stirrer and stored at room temperature (15 - 25 °C). Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Concentration in vehicle: 20, 60, and 200 mg/mL
- Amount of vehicle: 5 mL/kg bw/day
- Batch No.: 492194511, 103197718
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
On the first treatment day, samples of the control group as well as three samples (top, middle and bottom) of about 1 g of each concentration were taken prior to dosing for analysis of homogeneity and concentration. Samples of about 1 g of each concentration were taken 5 hours and 8 days after commencement of dosing to confirm stability.
The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to Harlan Laboratories Ltd. (Zelgliweg 1, 4452 Itingen / Switzerland) and stored there at -20 ± 5 °C until analysis. The samples were analyzed using a GC method provided by the Sponsor.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 - 20 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
15 days, until day 21 of gestation
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
Dose levels were based on the results of a foregoing range finding study, in which animals were orally exposed to 100, 300, and 1000 mg/kg bw/day for 15 days. No adverse effects were observed up to the limit dose of 1000 mg/kg bw/day. Therefore, 100, 300, and 1000 mg/kg bw/day were selected as the dose levels for the main study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (viability, mortality), once daily (clinical signs)

BODY WEIGHT: Yes
- Time schedule for examinations: daily from day 0 until day 21 post coitum

FOOD CONSUMPTION: Yes, recorded at 3-day intervals: days 0 - 3, 3 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18 and 18 - 21 post coitum
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on day 21 post coitum
- Organs examined: Any female sacrificed or found dead during the study was subjected to macroscopic examination with emphasis on the uterus and its contents. Post mortem examination, including gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, corpora lutea count and position of fetuses in the uterus was performed and the data recorded. The uteri (and contents) of all females with live fetuses were weighed during necropsy on day 21 post coitum to enable the calculation of the corrected body weight gain.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: If no implantation sites were evident, the uterus was placed in an aqueous solution of ammonium sulfide to accentuate possible hemorrhagic areas of implantation sites.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
The following statistical methods were used to analyze food consumption, body weights, reproduction and skeletal examination data:
- Means and standard deviations of various data were calculated and included in the report.
- The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
- Fisher's exact-test was applied if the variables could be dichotomized without loss of information.
Indices:
Pre- and post-implantation losses
Historical control data:
Historical control data from several former embryofetal development toxicity studies were provided, giving information on skeletal findings, visceral examination, and reproductive data.
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
All females survived until the scheduled necropsy on day 21 post coitum.
No clinical symptoms or signs were observed at any dose level during the study that were considered to be related to the test item.
No test item-related changes were observed in the amount of food consumed during the study.
Absolute body weight and body weight gain were not affected by treatment with the test item. Corrected body weight gain (corrected for the gravid uterus weight) was not affected by treatment with the test item (+13.2%, +14.6%, +13.1%, 13.4% in order of ascending dose level).
The relevant reproduction data (post-implantation loss and number of fetuses per dam) were not affected by treatment with the test item.
No findings were observed at any dose level during macroscopical examination.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No findings were observed during external examination of the fetuses in any group.
No test item-related effects on the sex ratio of the fetuses were noted in any group. The proportion of male fetuses was 52.9%, 46.4%, 53.2% and 49.1% in order of ascending dose level.
No test item-related effects on fetal body weights were noted. A marginal increase in group mean body weights of live fetuses calculated on an individual basis were seen for all test item treated groups when compared to controls, achieving statistical significance in groups 2 and 4. However, as the fetal weights were not statistically significant when calculated on a litter basis, were not dose-related, and since a toxicological effect is normally expected to cause a decrease in body weight, this was considered not to be a test item-related effect.

Visceral abnormalities and variations:
There were no findings seen during visceral examination that were considered to be related to maternal administration of the test item. Severe kidney pelvic dilatation was seen in one fetus in the group given 1000 mg/kg/day, and severely malpositioned testis was recorded for one fetus in the group given 100 mg/kg bw/day. However, as both instances were isolated findings, these were not considered to be test item-related.

Bone and cartilage abnormalities and variations:
No test item-related findings were observed.
Abnormalities were observed in 1 fetus from 1 litter at 100 mg/kg body weight/day (Skull bone supernumerary ossification site small or fused to the adjacent cervical vertebral archand; cervical and thoracic vertebral bodies/arches misshapen (partially split) / fused / absent). In addition abnormalities were observed in 2 fetuses from 2 litters at 1000 mg/kg bw/day (Skull bone supernumerary ossification site small or fused to the adjacent cervical vertebral arch; costal cartilage of cervical rib to thoracic rib fused). These abnormalities were all within historical background ranges and there was no dose-dependent pattern. Therefore the findings were considered to be incidental. Incidences of a long rib were observed in 3 fetuses from one litter. Since only 1 litter was affected, this was considered to be incidental.
Incidences of branched costal cartilage were seen in all treated groups, however were absent in controls. This was most prevalent in litters from the group administered 1000 mg/kg bw/day, with 5 fetuses (4%) in 4 litters (20%) effected. This incidence has been observed in this strain, and since no other bone effects have been observed this dose level, it is not considered to be a test item-related effect.
All other variations seen were considered to be incidental, with all values seen either within historical background ranges, non dosage related, at similar prevalence as seen in the controls or in a small number of fetuses spread between litters.

Ossification and supernumerary ribs:
No test item-related effects were observed. No statistically significance increases were observed in any of the findings at any dose level.

Additional cartilage variations:
There were no findings observed that were considered to be related to maternal administration of the test item. Although costal cartilage not reaching sternum was statistically significantly increased at 1000 mg/kg bw/day on a litter and on a fetus basis this incidence has been observed in this strain and is therefore not considered to be test item-related. All further findings were within the range of the historical control data or did not increase in a dose-dependent manner.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: corresponding to the highest dose tested
Abnormalities:
not specified
Developmental effects observed:
not specified

 

Group 1 (control)

Group 2 (100 mg/kg bw/d)

Group 3 (300 mg/kg bw/d)

Group 4 (1000 mg/kg bw/d)

Number of dams

22

22

20

20

Corpora Lutea

Mean ± St. dev.

309

14±2

298

13.5±2.4

252

12.6±2.3

278

13.9±1.7

Pre-Implantation Loss

% of Corp. Lutea

Mean ± St. dev.

Number of dams affected

10

3.2

0.5±0.9

6

13

4.4

0.6±1.2

7

13

5.2

0.7±1.0

7

4

1.4

0.2±0.5

3

Implantation Sites

% of Corp. Lutea

Mean ± St. dev.

299

96.8

13.6±1.8

285

95.6

13.0±2.8

239

94.8

12.0±2.9

274

98.6

13.7±1.9

Post-Implantation Loss

% of Impl. Sites

Mean ± St. dev.

Number of dams affected

6

2

0.3±0.5

6

5

1.8

0.2±0.5

4

6

2.5

0.3±0.7

4

3

1.1

0.2±0.4

3

Implantation sites scars

0

0

0

0

Embryonic/Fetal Deaths total

6

5

6

3

Embryonic Resorptions

5

5

5

2

Fetal Resorptions

1

0

1

1

Total Fetuses

% of Impl. Sites

Mean ± St. dev.

293

98

13.3±1.8

280

98.2

12.7±2.9

233

97.5

11.7±3.0

271

98.9

13.6±1.9

Live Fetuses

293

280

233

271

Dead Fetuses

0

0

0

0

Abnormal Fetuses

0

0

0

0

Total Males

% of Fetuses

155

52.9

130

46.4

124

53.2

133

49.1

Total Females

% of Fetuses

138

47.1

150

53.6

109

46.8

138

50.9

Weight of Fetuses (Litter Basis)

 

 

 

 

Total Fetuses

N (Litters)

Mean ± St. dev.

 

22

4.8±0.3

 

22

5.0±0.3

 

20

4.9±0.4

 

20

5.0±0.2

Total Fetuses

N (Fetuses)

Mean ± St. dev.

 

293

4.8±0.4

 

280

4.9±0.4**

 

233

4.9±0.5

 

271

5.0±0.4**

*/**: Dunnett-Test based on pooled variance significant at level 5% (*) or 1% (**)

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
No study on the ester of lanolin alcohols and fatty acids is available, as the substance is expected to be hydrolysed by esterases, the toxicity of the hydrolysis products lanolin alcohols and lanolin fatty esters is representative for the toxicity of the substance
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

The ester of lanolin alcohols and fatty acids is expected to be hydrolysed by esterases and is hydrolysed abiotically. Therefore the toxicity of the hydrolysis products lanolin alcohols and lanolin fatty esters is considered representative for the toxicity of the substance.

Justification for classification or non-classification

Based on the information available, the substance does not need to be classified for reproduction toxicity according to Regulation (EC) No 1272/2008 (CLP).

Additional information